Cardiovascular Department, the First Clinical HospitalDepartment of Pharmacology and Bio-pharmaceutical Key Laboratory of Heilongjiang Province and State, Harbin Medical University, Harbin, China.
Br J Pharmacol. 2012 Mar;165(6):1748-1756. doi: 10.1111/j.1476-5381.2011.01635.x.
Growing evidence suggests that long-term abuse of ketamine does harm the heart and increases the risk of sudden death. The present study was performed to explore the cardiotoxicity of ketamine and the protective effects of metoprolol.
Rats and rabbits were divided into control, ketamine, metoprolol alone and ketamine plus metoprolol groups. Ketamine (40 mg·kg(-1) ·day(-1), i.p.) and metoprolol (20 mg·kg(-1) ·day(-1), p.o.) were administered continuously for 12 weeks in rats and 8 weeks in rabbits. Cardiac function, electrophysiological disturbances, cardiac collagen, cardiomyocte apoptosis and the remodelling-related proteins were evaluated.
Rabbits treated with ketamine showed decreased left ventricular ejection fraction, slowed ventricular conduction velocity and increased susceptibility to ventricular arrhythmia. Metoprolol prevented these pathophysiological alterations. In ketamine-treated rats, cardiac collagen volume fraction and apoptotic cell number were higher than those of control animals; these effects were prevented by co-administration of metoprolol. Consistently, the expressions of poly (ADP-ribose) polymerases-1, apoptosis-inducing factor and NF-κB-light-chain-enhancer of activated B cells were all increased after ketamine treatment and sharply reduced after metoprolol administration. Moreover, ketamine enhanced sympathetic sprouting, manifested as increased growth-associated protein 43 and tyrosine TH expression. These effects of ketamine were prevented by metoprolol.
Chronic treatment with ketamine caused significant ventricular myocardial apoptosis, fibrosis and sympathetic sprouting, which altered the electrophysiological properties of the heart and increased its susceptibility to malignant arrhythmia that may lead to sudden cardiac death. Metoprolol prevented the cardiotoxicity of ketamine, indicating a promising new therapeutic strategy.
越来越多的证据表明，长期滥用氯胺酮会损害心脏，增加猝死的风险。本研究旨在探讨氯胺酮的心脏毒性作用以及美托洛尔的保护作用。
将大鼠和兔分为对照组、氯胺酮组、美托洛尔组和氯胺酮加美托洛尔组。大鼠连续 12 周、兔连续 8 周腹腔内注射氯胺酮（40mg·kg(-1)·d(-1)）和（20mg·kg(-1)·d(-1)）美托洛尔。评估心脏功能、电生理紊乱、心肌胶原、心肌细胞凋亡和重塑相关蛋白。
氯胺酮处理的兔左心室射血分数降低，心室传导速度减慢，室性心律失常易感性增加。美托洛尔可预防这些病理生理改变。在氯胺酮处理的大鼠中，心肌胶原容积分数和凋亡细胞数高于对照组；美托洛尔共给药可预防这些作用。同样，氯胺酮处理后多聚（ADP-核糖）聚合酶-1、凋亡诱导因子和 NF-κB-轻链增强子的 B 细胞激活表达均增加，而美托洛尔给药后表达急剧降低。此外，氯胺酮增强了交感神经发芽，表现为生长相关蛋白 43 和酪氨酸 TH 表达增加。这些氯胺酮的作用被美托洛尔所阻止。
慢性氯胺酮治疗可导致心室心肌明显凋亡、纤维化和交感神经发芽，改变心脏的电生理特性，增加恶性心律失常的易感性，可能导致心源性猝死。美托洛尔预防了氯胺酮的心脏毒性，提示了一种有希望的新治疗策略。
